Pyridine C(sp2)–H bond functionalization under transition-metal and rare earth metal catalysis

Pyridine is a crucial heterocyclic scaffold that is widely found in organic chemistry, medicines, natural products, and functional materials. In spite of the discovery of several methods for the synthesis of functionalized pyridines or their integration into an organic molecule, new methodologies for the direct functionalization of pyridine scaffolds have been developed during the past two decades. In addition, transition-metal-catalyzed C–H functionalization and rare earth metal-catalyzed reactions have flourished over the past two decades in the development of functionalized organic molecules of concern. In this review, we discuss recent achievements in the transition-metal and rare earth metal-catalyzed C–H bond functionalization of pyridine and look into the mechanisms involved.


Introduction
Pyridine, one of the most important azaheterocyclic scaffolds, is found in a diverse range of bioactive natural products, pharmaceuticals, and functional materials [1][2][3][4][5][6][7][8][9][10]. Due to its different characteristics such as basicity, stability, water solubility, small molecular size, and ability to form hydrogen bonds, pyridine continues to be a suitable moiety in organic synthesis. In addition, it has been observed that pyridine rings serve as bioisostere for aromatic rings, amines, amides, and N-containing heterocycles. Due to the aforementioned qualities, numerous U.S. FDA-approved medications have pyridine scaffolds in their molecules (Figure 1).
In this context, the synthesis of the pyridine motif is always there in trend. Many pyridine syntheses have relied on the con- densation of carbonyl compounds and amines for a very long time [11]. The classical methods for the synthesis of functionalized pyridine include the Hantzsch pyridine synthesis and the Bohlmann-Rahtz synthesis (Scheme 1a and b). Furthermore, alternative methodologies are being developed for the synthesis of functionalized pyridines or its integration into an organic molecule [12][13][14][15][16][17][18][19][20]. Although classical organic synthesis is incredibly effective, it frequently requires the prefunctionalization of substrates and involves stoichiometric waste.
The challenges associated with the functionalization of pyridine are based on the low reactivity of the pyridine ring system for undergoing substitution reactions. This is attributed to the electron-deficient nature of the ring system due to the presence of the sp 2 -hybridized nitrogen atom. In addition, the lone pair electrons of the nitrogen atom interact with Lewis acids instead of the π-electrons of the ring system thus resulting to its reduced reactivity for electrophilic aromatic substitution reactions, such as a Friedel-Crafts reaction [21][22][23]. Hence, it is challenging to functionalize a C-H bond in pyridine with traditional chemical transformations. On the other hand, intriguing developments have been made for the functionalization of inert C-H bonds in organic synthesis during the past two decades. In this regard, the transition-metal-catalyzed C-H functionalization has made its way towards the synthesis and functionalization of various complex organic molecules [24][25][26][27][28][29][30][31]. In addition, rare earth metal-catalyzed C-H functionalization reactions have been known for a few decades, however, they received growing interest only recently [32][33][34]. Thus, diversely functionalized pyridines have been synthesized via C-H activation under transition-metal and rare earth metal catalysis, including C-H alkylation, alkenylation, arylation, heteroarylation, borylation, etc. Recently, metal-free approaches have also been developed for the C-H functionalization of N-heterocycles [35][36][37][38][39]. However, due to the vastness of reports on C-H functionalizations of N-heterocycles, in this review we have summarized recent progress (from year 2010 to 2023) in the C-H functionalization of the pyridine ring only. Herein, we discuss transition-metal as well as rare earth metal-catalyzed directed and undirected, proximal as well as distal pyridine C(sp 2 )-H bond functionalizations in detail under different types of reactions. Further, this review excludes the use of pyridine as a directing group for C-H functionalizations and the C-H functionalization of fused pyridines.

Review C-H Alkylation of pyridine
The C-H bond is the backbone of an organic molecule and the conversion of a C-H bond to a C-X bond (X = carbon or heteroatom) forms the basis in organic synthesis. The functionalization of C-H bonds is challenging due to a large kinetic barrier for C-H bond cleavage and also achieving selectivity is difficult due to its ubiquitous nature [40]. The metal-catalyzed C-H bond functionalization is a good strategy for synthesizing highly functionalized organic frameworks. In this context, the C-H alkylation is one of the most important C-C bond-formation reactions [41][42][43][44][45]. On the other hand, a metal-catalyzed functionalization of arene/heteroarene C-H bonds to the corresponding C-C bonds is an area of great interest and has been well studied [46,47]. Pyridine, being an important heterocyclic scaffold, various studies have been conducted for the C(sp 2 )-H alkylation of the pyridine ring. In this part, we describe pyridine C-H alkylation reactions sub-sectioning based on the position of the alkylation reported.

ortho-C-H Alkylation
Inspired by the pioneering work of Jordan and co-workers [48] on the ortho-selective C-H alkylation of 2-picoline with propene using a cationic zirconium complex under a H 2 atmosphere in 1989 and the work done by Bergman and Ellmann [49] in 2010 for the ortho-C-H alkylation of pyridines under Rh(I) catalysis at high temperature, in 2011 Hou and Guan reported an atom economical method for the selective ortho-alkylation of pyridines by C-H Scheme 2: Rare earth metal (Ln)-catalyzed pyridine C-H alkylation. addition to olefins under cationic half-sandwich rare-earth catalysis [50]. They carried out the reaction in the presence of dialkyl complexes of scandium (Sc) or yttrium (Y) such as (C 5 Me 5 )Ln(CH 2 C 6 H 4 NMe 2 -o) 2 (Ln = Sc, Y) in combination with B(C 6 F 5 ) 3 as an activator. The method demonstrated a wide substrate scope of both pyridines and olefins including α-olefins, styrenes, and conjugated dienes. The yttrium complex was found to be superior as compared to the scandium complex for the alkylation reaction of bulkier 2-tert-butylpyridine with ethylene. In addition, the yttrium catalyst was also found to have a higher catalytic activity for the ortho-alkylation of pyridines with styrenes to give the linear alkylated products (5b,c, Scheme 2). Further, the authors proposed that the C-H bond activation could be the rate limiting step based on kinetic isotope experiments (KIE). The proposed mechanism involves the coordination of pyridine to the metal center of the cationic catalyst and B(C 6 F 5 ) 3 promotes the ortho-C-H activation (deprotonation) of pyridine to afford pyridyl species 6. Next, the 2,1-migratory insertion of alkene 2 into the metal-pyridyl bond in 6 gives the intermediate 7, which on subsequent deprotonation gives the branched alkylated product 4. Whereas, in case of styrene 3 a 1,2-insertion takes place possibly due to the formation of the stable benzallylic species 8, which on deprotonation gives the linear alkylated product 5.
The C-H activation/C-C cross-coupling reaction with 1° alkyl electrophiles has been known in the past, however, the C-H alkylation with nonactivated secondary (2°) alkyl electrophiles and tertiary alkyl electrophiles was little known. In this context, in 2013, Fu and co-workers came across an unexpected finding with Pd-catalyzed C-H activation/C-C cross-coupling of pyridine N-oxides with nonactivated secondary (2°) alkyl bromides [51]. The cross-coupling is difficult to achieve as the Pd-catalyzed S N 2 process is sensitive towards the steric bulk of the secondary or tertiary alkyl electrophiles. The optimized conditions for the ortho-alkylation of pyridine N-oxides 9 with nonactivat-Scheme 3: Pd-catalyzed C-H alkylation of pyridine N-oxide.

Scheme 4:
CuI-catalyzed C-H alkylation of N-iminopyridinium ylides with tosylhydrazones (A) and a plausible reaction mechanism (B). ed secondary (2°) alkyl bromides 10 required 5 mol % of the Pd(OAc) 2 dppf catalyst, Cs 2 CO 3 (2.0 equiv) as base in toluene at 100 °C as shown in Scheme 3. Under these conditions, the reaction provided diverse 2-alkylpyridine derivatives 11 in moderate to good yields starting from both cyclic and acyclic alkyl bromides. The findings of the reaction's stereochemistry and observations made during some cyclization or ring-opening reactions indicated that the C-H alkylation may proceed through a radical-type mechanism. Next, in 2013, Wang and co-workers [52] reported a protocol using CuI (10 mol %) as inexpensive catalyst and LiOt-Bu (3.5 equiv) as the base for the C-H alkylation of N-iminopyridinium ylides 12 with N-tosylhy-drazones 13 showing good substrate scope for both coupling partners (Scheme 4). A substituent on the aromatic ring of the tosylhydrazones did not significantly affect the C-H alkylation reaction and the reaction also proceeded well with hydrazones 13 obtained from aliphatic aldehydes or ketones. Based on mechanistic experiments and DFT calculations, the reaction presumably proceeds via a Cu-carbene migratory insertion (Scheme 4b). In the presence of CuI and the base the initial direct C-H activation of the ylide 12 gives the copper pyridinium ylide 15. The latter reacts with the diazo compound formed through reaction of hydrazone 13 with the base to give the copper-carbene species 16. Then, the intermediate 16 undergoes a Cu-carbene migratory insertion giving intermediate 16', which upon protonation gives the desired alkylated product 14.
Later, in the year 2018, Yao and co-workers [53] developed the first example of a group 4 metal-based catalyst protocol for the C-H alkylation of pyridine 1 with alkenes 18 and 20 as cou-pling partners. They demonstrated that the reaction in the presence of cationic zirconium complexes derived from zirconium dibenzyl complexes bearing tridentate [ONO]-type aminebridged bis(phenolato) ligands and [Ph 3 C][B(C 6 F 5 ) 4 ] (Scheme 5), gave rise to ortho-selective C-H alkylated pyridines 19 and 21. It was observed that the cationic Zr complexes provided good transformations, probably due to good Scheme 6: Rare earth metal-catalyzed pyridine C-H alkylation with nonpolar unsaturated substrates. accessibility of the coordination site and an increased Lewis acidity of the metal center. The authors also demonstrated that this catalytic system also catalyzes the alkylation of benzylic C-H bonds (C(sp 3 )-H) of various dialkylpyridines with alkenes. It is to be noted that the ligands' backbones were found to be crucial for the regioselectivity of the addition to benzylic C(sp 3 )-H bonds, as N-arylamine-bridged bis(phenolato) Zr complexes provided branched products whereas N-alkylaminebridged bis(phenolato) Zr complexes provided the linear addition products. The proposed mechanism (Scheme 5b) involves the initial formation of In the same year, Tsurugi and Mashima reported the use of rare earth metal complexes for the insertion of nonpolar unsaturated substrates (C=N) into the ortho-C-H bond of pyridine derivatives [54]. They carried out the C-H aminoalkylation of pyridines 1 using yttrium complex 26 with nonactivated imines 25 (Scheme 6). The authors also demonstrated the enantioselective aminoalkylation, using chiral diamines as ligands. The introduction of chiral diamines in the metal complex produced the aminoalkylated products enantioselectivity with good ratio of enantiomeric excess. The plausible mechanism involves the formation of (dibenzylamido)yttrium complex 28 by the reaction of yttrium complex 26 with HNBn 2 . Then σ-bond metathesis between the Y-N bond of 28 and the ortho-C-H bond of pyridine gives η 2 -pyridyl species 29 which on imine insertion produces species 30. Subsequent protonation then provides the aminoalkylated product 27 (Scheme 6b).
The selective C-H monoalkylation of pyridines with alkenes is a challenging task. Most ortho-C-H alkylation reactions have been achieved starting from C2-substituted pyridines. There are a few studies reported for the selective C-H monoalkylation of unsubstituted pyridines, which, however, displayed limited substrate scope [55,56]. In this regard, in 2021, Nakao and co-workers [57] reported a selective C2-monoalkylation of 2,6unsubstituted pyridines with alkenes 31 using a heterobimetallic Rh-Al catalyst. The reaction provided the linear product 32 with aliphatic alkenes 31, whereas vinylarenes produced the branched product 33 and also alkenylated products 34. The reaction gave excellent yields of the ortho-alkylated products with good functional group tolerance (Scheme 7).
The C-H functionalization of pyridines through action of different catalyst systems including transition metals and rare earth metals has been described and some other organometallic  systems also were shown to have catalytic reactivity. Adopting this catalytic reactivity of organometallics and also the special bidentate nature of phosphinoamide ligands, in 2021, Chen and group [58] described the catalytic ortho-C(sp 2 )-H functionalization of pyridines with polar imines 35 and nonpolar alkenes 37 by using mono(phosphinoamido)-ligated rare earth complexes (NP2-Gd and NP1-Sc) as shown in Scheme 8. Complex NP2-Gd was found to be effective in the functionalization of pyridines with imines providing various ortho-aminoalkylated products 36 whereas ortho-alkylated pyridine derivatives 38 were obtained when using NP1-Sc as the catalyst (Scheme 8).
Attributing to the strong coordination of unsubstituted pyridine with Rh(I) catalysts, C-H alkylations of pyridine lacking orthoblocking groups is a challenge. In this context, a regioselective alkylation of ortho-unsubstituted or substituted unactivated pyridines with acrylates and acrylamides under Rh(I) catalysis has been demonstrated by Ellman and co-workers [59]. The Scheme 9: Rhodium-catalyzed pyridine C-H alkylation with acrylates and acrylamides. authors observed that in the presence of [Rh(cod)Cl] 2 as catalyst, dppe as ligand, and potassium pivalate (KOPiv) as base, linear C-H-alkylated products 40 were obtained from both acrylates and acrylamides in moderate to high yields (Scheme 9, reaction conditions a). However, when K 3 PO 4 was employed as the base under otherwise identical conditions, the authors observed a switch in regioselectivity and branched products 41 were obtained with acrylamides as coupling partners (Scheme 9, reaction conditions b). Thus, the authors demonstrated a switch in regioselectivity (linear/branched) which was controlled exclusively by the base used. During further investigations the authors found that the use of ligand dArFpe at reduced reaction temperature resulted in a significant increase in the yield of the branched alkylated product 41 (Scheme 9, reaction conditions c) compared to using the ligand dppe (Scheme 9, reaction conditions b). Moreover, when ethyl meth-acrylate was used as the coupling partner under the reaction conditions c, branched alkylated products 41' were obtained selectively in high yields (Scheme 9). A high functional group tolerance was observed in both linear and branched alkylated products.
It is known that the strong coordination of the nitrogen atom in pyridine rings with metals inhibits the metal-chiral ligand coordination, thus making the C-H alkylation of pyridine substrates challenging. In addition, transition-metal-catalyzed enantioselective C-H alkylation reactions of pyridine still remain a great challenge. In this regard, in 2022, Ye and co-workers [60] reported for the first time an enantioselective C-2 alkylation of pyridine using a chiral phosphine oxide-ligated Ni-Al bimetallic catalyst system and the protocol was found effective for a wide range of pyridines including unsubstituted pyridines, C2, C3 and C4-substituted pyridines and complex pyridines containing bioactive molecules (Scheme 10). To attain enantioselectivity a chiral phosphine oxide (43)-ligated Ni-Al bimetallic catalyst was used that was critical in improving the reactivity and controlling the selectivity of the reaction. Further, based on deuterium labelling experiments, KIE studies, and DFT calculation, a plausible mechanism (Scheme 10b) has been proposed. Initially, a reversible ligand-to-ligand H-transfer process occurs for C-H activation between the intermediates 46 and 47. Next, isomerization of the η 1 -allyl complex 47 forms the η 3 -allylic nickel complex 48, which on reductive elimina-tion delivers the desired product 44 via the intermediate 49 (Scheme 10b). It was proposed that the enantioselectivity was mainly due to the C-C reductive elimination of the R-pathway, which is lower in energy than the S-pathway.

Remote C-H alkylation
Several remarkable studies have been reported for proximal C-H functionalizations in pyridine substrates under different catalytic systems. However, the intermolecular undirected distal C-H functionalization in pyridine remained unstudied. In these circumstances, the distal C-H alkylation by addition of the pyri-Scheme 11: Iridium-catalyzed pyridine C-H alkylation.
dine C-H bond to an aldehyde 50 under iridium catalysis was achieved by Shi [61] in 2010 through an unusual meta-selectivity for the first time (Scheme 11a). To achieve meta-selectivity, the group has screened various transition metals and revealed that a silyl-iridium complex promoted the addition of meta-pyridyl C-H bonds to aldehydes 50 which resulted in C3-alkylated pyridines 51. Based on the reactions performed for the catalytic activity of the silyl-iridium complex, the authors proposed a catalytic mechanism (Scheme 11b). The mechanism involves the initial formation of the active silyl-iridium catalyst A which through oxidative addition of 1 gives the silyl-iridium complex 52. The insertion of aldehyde 50 into the Ir-Si bond of 52 provides the pyridyl alkyl iridium species 53 that finally by C-C formation via reductive elimination furnishes the desired products 51 along with the formation of an iridium hydride species (Scheme 11b).
A direct selective C4-alkylation of pyridine has been reported by the groups of Hiyama [62] (Scheme 12a) and Zhang [63] (Scheme 12c) in 2010 and 2020, respectively. The Hiyama group developed a C-4-selective alkylation of pyridines using a Ni/Lewis acid cooperative catalytic system in combination with a bulky N-heterocyclic carbene ligand and (2,6-t-Bu 2 -4-Me-C 6 H 2 O) 2 AlMe (MAD) as the Lewis acid which allowed the direct C-4 alkylation of pyridines 1 (Scheme 12a). With the optimized reaction conditions in hand the group also screened the alkene and pyridine substrate scope which resulted C4-alkylated products 55 in moderate to high yields. A possible mechanistic cycle (Scheme 12b) was also proposed, comprising an initial formation of η 2 -arenenickel species 56A, which undergoes oxidative addition to the C(4)-H bond of pyridine to form intermediate 56B. Next, coordination and migratory insertion of the alkene provides the intermediate 57 which on subsequent reductive elimination furnishes the C4-alkylated products 55. Based on the deuterium exchange experiment, the author suggested that the steps involved in the catalytic cycle from 56A to 57 are reversible in nature, which may activate the C2 or C3 position as well. However, the reductive elimination at the C4-position was suggested to be irreversible in nature and does not takes place at the C2 and C3 position. On the other hand, the Zhang group reported the C4 alkylation of pyridines using alkenes 58 catalyzed by an organoborohydride (NaBEt 3 H) and aided by organoboranes (Scheme 12c). The proposed mechanism (Scheme 12d) involves the formation of the organoborate intermediate 60 from alkene 58 in the presence of the NaBEt 3 H catalyst and the organoborane. Next, the organoborane-activated pyridine species 61 undergoes an addition reaction regio- Further enantioselective pyridine C-H alkylation reactions are very scarcely reported which specifically include the intramolecular C-H alkylation of pyridine with alkenes at the C3 or C4 positions. Hence, very recently in 2022, Shi and co-workers [64] adopted an intermolecular process and reported the enantioselective para-alkylation of pyridines with styrenes 64 using a Ni-Al bimetallic system and NHC ligand 65 through intermolecular hydroarylation with high levels of enantio-and regioselectivity in the alkylated products 66 (Scheme 13). Also, the authors performed DFT studies revealing the reaction mechanism and supported that the interaction of the NHC aryl part with trans-styrene was highly important for the reaction to proceed and for the enantiocontrolled formation of the products.

Alkenylation
The C-H alkenylation is another important C-C bond-forming reaction. Olefinated organic molecules like vinylarenes play a significant role as key intermediates in organic synthesis and are also present in various natural products as well as drug molecules [65][66][67][68]. Though there are traditional methods available for C-H olefinations they suffer from some disadvantages such as for example requiring prefunctionalized substrates as in case of the Heck cross-coupling [69,70]. However, researchers have developed various methods for the transition-metal-catalyzed C(sp 2 )-H olefination using various types of alkenes as coupling partners [71][72][73]. This part of the review covers reports for the alkenylation of pyridine with terminal alkynes, acrylates, allenes, and alkynes as coupling partners achieving the functionalized C(sp 2 )-H-olefinated pyridine frameworks via metal catalysis.

ortho-C-H Alkenylation
In 2012, Huang and co-workers [74] disclosed a ligand-free oxidative cross-coupling reaction of pyridine with acrylates, acrylamides, and styrenes (Scheme 14). Their preliminary investigation provided both C2 and C3-olefinated products, with the C2-selective product 69 as the major product (Scheme 14a). With the optimized conditions of Pd(OAc) 2 (10 mol %), AgOAc (3 equiv), PivOH (2.5 equiv) in DMF, the method showed wide substrate scope and good yields. Based on the experimental findings the authors proposed a catalytic cycle (Scheme 14b) which commences with the coordination of Pd(II) with the pyridine nitrogen to provide intermediate 70. In the same year, Ramana and Goriya [75] proposed an unexpected C-6 (C-2)-propenylation reaction of pyridine in the presence of allyl bromide (73) and a Ru catalyst using 2-arylpyridines (Scheme 15). Earlier reports described the propenylation took place on the ortho-position of the phenyl ring [76,77], whereas this group achieved the propenylation of the pyridine moiety. The authors screened different allyl halides and Ru complexes as catalysts. With the optimized conditions in hand, diverse 2-arylated pyridines were screened resulting in the corresponding products 74 in good yields. Allene, a cumulated diene and an important building block in organic synthesis has versatile biological properties and is also an important subunit in various natural products and pharmaceutical compounds [78]. Allenes have been applied as useful substrates for the alkenylation of organic molecules [79]. There are various reports for the C-H alkenylation of aromatic C-H bonds using allenes [80]. To this end, Hou and group in 2015 [81] demonstrated the C-H allenylation of pyridines with excellent substrate scope using a scandium catalyst (Scheme 16). A vast number of pyridines and allenes were studied as substrates to provide the C2-alkenylated pyridines in good to high yields. Based on the mechanistic experiments a possible catalytic cycle has been proposed (Scheme 16b). While speaking regarding the alkenylation, the geometrical isomerism, i.e., the stereoselectivity between the cis-and transalkenylation, has not been considered so far. Except lately, in 2020, Chen and group [82] reported a Pd/Cu-catalyzed regioand stereoselective synthesis of C2-alkenylated pyridines starting from internal alkynes 84 and pyridinium salts in a stereodivergent manner (Scheme 17a). The interesting part of this work was the switching of the alkene configuration of the products by modifying the substituents on the nitrogen of the pyridinium salts. Further, the method showed a wide substrate scope for both the Z-and E-alkenylated products in which Z-selectivity was achieved when N-methylpyridinium salts were used and E-selectivity when N-benzylpyridinium salts were used.
In the proposed mechanism (Scheme 17b) the E-and Z-isomers can be assessed through point at which dealkylation occurs, i.e., if it occurs as last step the Z-isomer 85 is obtained and if it

Remote alkenylation
In 2011, a study for weakening the strong coordination of the pyridyl N-atom with Pd in the presence of a bidentate ligand was reported by Yu and co-workers [83]. They showcased the C3-selective olefination of pyridines using 1,10-phenanthroline, a bis-dentate ligand that weakens the coordination of the Pd catalyst with the pyridyl N-atom through the trans-effect (Scheme 18). The trans-effect is the switching of the metal coordination between the π-ring system and the hetero-(nitrogen) atom of pyridine [84,85]. In comparison to coordination with nitrogen, which is strong in nature, the coordination with the ring is weaker and cleavable. The usage of a bidentate ligand will enhance the trans-effect and shift the coordination towards the ring (Scheme 18b).
There are numerous studies reported for directing group or chelate-assisted metal-catalyzed C-H functionalization reactions. However, non-chelate-assisted or undirected C-H functionalizations under ligand-controlled conditions are underexplored. Hence, differentiating from this co-coordinative model, in 2013, Zeng and co-workers [86] reported the MPAA (mono-N-protected amino acids) ligand-promoted non-chelate-assisted C-H activation via Pd-catalyzed dehydrogenative Heck reactions on pyridines with simple alkenes 96, leading to the C3-alkenylated products 97 (Scheme 19). The reaction was based on the previous reports of using of the MPAA ligands in the Pd-catalyzed oxidative cross-coupling reactions discovered by Yu et al. [87]. When 2-methoxypyridine was screened, the reaction resulted in a mixture of C3-and C5-selective C-Hfunctionalized products 97f and 97f' in a regioisomeric ratio of nearly 1:1. Further, during the substrate scope study, when 1,1′disubstituted butyl methacrylate was used as coupling partner a mixture of 97g and the isomeric product 97g' was observed in 42% yield. [RhCp*Cl 2 ] 2 (5 mol %), AgSbF 6 (20 mol %) in DCE at 120 °C, Cu(OAc) 2 was found crucial for the transformation in comparison to other additives and showed good substrate scope while unactivated alkenes like styrene resulted in no reaction. Also, the authors successfully applied the developed protocol to a multigram-scale synthesis of compound 101, a tricyclic imidazonaphthyridinone derivative having antibacterial properties, with low catalyst loading (0.1 mol %) (Scheme 20b). Later, in 2014, the same authors, using an amide as directing group (DG), developed a protocol for the regioselective C3-alkenylation of pyridines through syn-addition of alkynes, displaying broad substrate scope and high yields (Scheme 20c). Nitrogen heterocyclic carbenes (NHCs) are of central importance in organometallic chemistry and in organic synthesis.
Also, metal-NHC complexes have wide application in catalysis and various organic transformations and a range of metal-NHCs served as catalysts. In 2010, using NHC ligands, Yap and co-workers [90] developed a method for the direct para and meta-C-H alkenylation of pyridines with 4-octyne (107) using a nickel Lewis acid catalyst with amino pendant linked NHC complex (Scheme 21). In addition, the authors were able to isolate the bimetallic intermediate structure η 2 ,η 1pyridine-Ni(0)-Al(III) complex 112, as a support for their mechanism for the para-C-H functionalization. They further investigated the scope and limitations of the dual catalyst Ni-AlMe 3 and also the sensitivity of the reaction towards the steric environment on the pyridine ring. The complex 112 undergoes oxidative addition followed by an alkyne insertion reaction to give intermediate 113, which after reductive elimination provides the alkenylated product 109 (Scheme 21b).

Arylation C-2 Arylation
Owing to the remarkable role of aromatic C-H arylation reactions in organic synthesis abundant methods have been reported for aromatic C-H arylations using different arylating coupling partners, such as for instance, aryl halides. In 2014, Scheme 22: Arylboronic ester-assisted pyridine direct C-H arylation.
using organoboron coupling partners, Wu and co-workers [91] reported a protocol for the Cu-catalyzed C-H arylation of pyridine N-oxides 9 with arylboronic esters 114 and prepared C2-arylated pyridines 115 in moderate to good yields (Scheme 22). By using an inexpensive Cu catalyst, the method allows for the simple and practical synthesis of 2-arylpyridines. The reaction starts with the formation of arylated pyridine N-oxide 116 by reaction of pyridine N-oxide 9 with the arylboronic ester 114 in the presence of Cu catalyst and base which is followed by deoxygenation to furnish the desired product 115 (Scheme 22b).
In 2015, a palladium-catalyzed cross dehydrogenative coupling of pyridine N-oxides with toluene for the regioselective arylation and benzylation of pyridine N-oxide was reported by Khan and co-workers [92] (Scheme 23). The authors have shown toluene 117 when used as benzyl and aryl source remained intact under the reaction conditions without any further oxidation. Different oxidants resulted in different products such as the monoarylated product 118 formed in the presence of TBHP as oxidant and the benzylated product 119 was obtained when potassium persulfate was used. Interestingly, aza-fluorene N-oxide 119b was formed during benzylation of 2-ethylpyridine N-oxide. A possible mechanism has also been reported (Scheme 23b). Electrophilic palladation at the C2-position of pyridine N-oxide 9 provides intermediate 120. The radical intermediate 121 is generated in situ by H-atom abstraction from toluene 117 by sulfate radical anion. Coordination of intermediate 120 and 121 leads to complex 122 which undergoes reductive elimination to provide product 119. 2-Ethylsubstituted pyridine N-oxides may undergo a dual C-H activation due to the buttressing effect of the ethyl group to produce azafluorene N-oxide 119b.
In 2016, Wei and co-workers [93] reported the arylation of pyridine N-oxides 9 employing potassium (hetero)aryltrifluoroborates 126 as coupling partner using palladium acetate and TBAI (Scheme 24). Electron-withdrawing and donating groups on the pyridine N-oxide 9 resulted in the corresponding C2-arylated products 127 in good to excellent yields with high site selectivity. A catalytic mechanism was proposed in which the electrophilic C-H palladation of pyridine N-oxide 9 occurs preferentially at the C-2 position leading to heterocoupling intermediate 128. Subsequent transmetalation provides the arylpalladium intermediate 129 which after reductive elimination furnishes the desired product 127.

C-3 Arylation
In 2011 and 2013, the groups Yu [95] and Tan [96], reported a ligand-assisted distal arylation selectively taking place at the meta-position in pyridine. Both groups used Pd(OAc) 2 as cata- Almost at the same time, Yu and co-workers reported the selective Pd(0)/PR 3 -catalyzed C3 or C4-arylation of nicotinic and isonicotinic acids using amide as a directing group (Scheme 27) [97]. This method provides a way for arylated nicotinic acid derivatives which serve as building blocks for biologically important molecules. This was the first report for a directing group-Scheme 25: Transient activator strategy in pyridine C-H biarylation.
assisted C3/C4-arylation of pyridines. The authors screened various N-arylamide directing groups 144 out of which N-phenylamide was found to be the better directing group. Then, the authors screened various nicotinic and isonicotinic acids which afforded the desired products 145 and 146 in good yields generating a library of isonicotinic and nicotinic acid derivatives.
Another inexpensive and non-toxic iron-catalyzed C-H arylation of pyridines has been reported by DeBeof and co-workers [98]. Using the imine in 147 as directing group, afforded the arylated pyridine products 150 in good to high yields (Scheme 28). In this reaction, Grignard reagent 148 was used as arylation source in excess amount as the reagent underwent homocoupling leading to the formation of biaryl systems under the reaction conditions. 1,2-Dichloro-2-methylpropane (149) was found to be an effective oxidant under the reaction condi-tions. Also, the additive KF was employed in order to minimize the oxidative iron-catalyzed homocoupling of 148. An imine directing group at the para-position in pyridine 147 lead to activated ortho-position products 150 within 15 minutes. The imine group of the products can further be hydrolyzed to get the corresponding ketones.
In 2018, Albéniz and group [99] reported the direct C3-arylation of pyridines with the help of bipy-6-OH as coordinating ligand under palladium catalysis (Scheme 29). In most of the cases the arylated pyridines 152 were obtained as mixtures of ortho-/meta-/para-substitution, however, the authors found that the yield of the meta (C-3)-arylated pyridines were drastically higher, thereby showcasing the regioselectivity of the reaction. The chelating anionic ligand acted as base in the catalytic cycle, allowing for the oxidative addition of the arene to the Pd complex. The proposed mechanism (Scheme 29b) involves the oxi-

Heteroarylation C-2 Heteroarylation
Heteroaryl groups are a common core in natural products and pharmaceuticals. In addition, the heterodiaryl systems widely occur in biologically important organic molecules, dyes, fragrances, advanced materials, and agrochemicals as well. Thus, the functionalization of the pyridine core with a heterocycle is a desirable transformation in organic synthesis. Manickam and co-workers [100] carried out a palladium-catalyzed decarboxylative ortho-(hetero)arylation of pyridine N-oxides 9 with heteroarylcarboxylic acids 156 (Scheme 30). The reaction showed good compatibility with various functional groups. The proposed mechanism (Scheme 30b) involves the silver-catalyzed decarboxylation of heteroaryl acid 156 followed by transmetalation providing palladium intermediate 160. Later in 2014, Kuang and co-workers [101] developed a highly efficient and regioselective oxidative cross-coupling of pyri-dine N-oxides 9 with five-membered heterocycles 162 and 163 through a two-fold C-H activation under palladium catalysis. Silver carbonate and 2,6-lutidine were found to be an effective base and ligand, respectively, for providing the desired products 164 and 165 in good yields (Scheme 31).
In 2015, an economic route for copper-catalyzed biaryl coupling of azine(pyridine)-N-oxides 9 with oxazoles 166 was reported by Miura and group [102]. Although their work majorly covered quinoline N-oxide substrates, they also investigated three pyridine substrates in the reaction leading to the corresponding products in moderate yields (Scheme 32). The N-oxide plays a role as an activator and is subsequently eliminated via deoxygenative elimination furnishing the C-2-functionalized pyridines 167. The reaction mechanism (Scheme 32b) involves the initial C-H-cupration of 166 producing an oxazolyl-copper intermediate 168. Nucleophilic addition fol-lowed by C-H activation of 9 provides the hydroxy copper species 169, which on deoxygenative elimination furnishes the desired product 167.

C-3 Heteroarylation
In 2013, Su and co-workers [103] developed a catalytic methodology for the distal heteroarylation of pyridines 170 via Rh(III)catalyzed dehydrogenative cross-coupling showcasing a good substrate scope (Scheme 33). Initially, their investigation involved evaluating the reaction between N-phenylisonicotin-amide 170 and 2-methylthiophene 171 which resulted in the desired product 172. The plausible mechanism (Scheme 33b) starts with the initial coordination of the pyridine directing group 170 with rhodium providing a five-membered rhodacyclic intermediate I which further forms the aryl-rhodium(III) complex II by reaction with 171. Subsequently, this intermediate undergoes reductive elimination from the rhodium(III) center to furnish the desired ortho-C-H-arylated product 172 releasing a Rh(I) species. The Rh(III) species is regenerated in the presence of the copper salt.  In another case of C3-(hetero)arylation, Yu and group [104] using palladium for C-H activation of pyridine with phenanthroline as a ligand developed a method in 2016 (Scheme 34). The authors achieved both arylation and heteroarylation at the C-3-position in pyridine and showcased the formation of bipyridines 174. The mechanism is depicted in Scheme 34b, where the complex A undergoes C3-H activation to provide intermediate 176 which similarly undergoes one more step of C-H activation to provide the bi(hetero)arene-Pd(II) species 177 which undergoes reductive elimination furnishing the desired products 174/175.

C-H Annulation of pyridine to fused heterocycles
Annulation reactions in organic synthesis have achieved great attention toward the construction of various carbocycles and heterocycles. These annulations can be either intermolecular or intramolecular and various substrates have been studied resulting in diverse products. Pyridine has been also reported for the construction of pyridine-fused heterocycles via C(sp 2 )-H functionalization and further annulation. In this aspect, considering the use of pyridines for the formation of quinolines and isoquinolines, an oxidant-dependent rhodium-catalyzed C-H annulation of pyridines with alkynes was reported by Li and co-workers [105] in 2011 for the direct synthesis of quinolines 180 and isoquinolines 181 involving a two-fold C-H activation of pyridine at the C2 and C3 position (Scheme 35a). Further, during optimization when silver additives like Ag 2 CO 3 , Ag 2 O, and AgOAc were used the reaction resulted in the formation of isoquinoline derivative 181. In addition, the reaction showed high regioselectivity in the presence of unsymmetrical alkynes 179. Different directing groups 178 were employed resulting in diversified products 180. The proposed mechanism (Scheme 35b) involves coordination of rhodium with isonicotinamide 178 and subsequent ortho-C-H activation generating the five-membered rhodacycle 183. Next, first alkyne 179 insertion results in the five-membered rhodacycle 184 which is followed by a second regioselective insertion of alkyne 179 into the Rh-C bond of 184 providing the seven-membered cyclic intermediate 185. Further reductive elimination furnishes the quinoline product 180 and a Rh(I) species, with the latter being oxidized by Cu(II) to complete the catalytic cycle.
Next, considering the role of N-heterocyclic carbene (NHC) ligands acting as directing group as well as functionalizing unit in arene C-H functionalization reactions with alkynes, Choudhury and group [106] in 2015 developed a protocol for the intermolecular C-H annulation of NHC-substituted pyridines with a variety of internal alkynes 187 under rhodium catalysis for the synthesis of annulated and highly decorated pyridines 188 (Scheme 36). The authors used the N-heterocyclic carbene ligand as directing group to prepare imidazo[1,2-a] [1,6]naphthyridine motifs 188 as desired products. Based on the experimental results and annulation chemistry a catalytic mechanism has been proposed (Scheme 36b) that involves the C3 hydrogen of pyridine undergoing a cyclorhodation with the catalyst in the presence of NaOAc, directed by in-built NHC ligand coordination to provide intermediate 189. Out of various pyridine-fused heterocyclic hybrids, azaindolines are important scaffolds in natural products and pharmaceuticals serving different biological activities. Hence, looking at the importance of azaindolines in drug discovery a protocol of rare earth metal-catalyzed intramolecular insertion of the pyri-dine C-H bond into unactivated vinyl C-H bonds has been developed by Chen and co-workers [108] (Scheme 38). Using this protocol azaindolines 205 were accessed in moderate to excellent yields and also naphthyridine derivatives (205k and 205l) were synthesized. In the proposed mechanism, the initial depro-

C(sp 2 )-H Functionalization of pyridine rings in bipyridine systems
The functionalization and synthesis of bipyridine derivatives is of great interest and importance in synthetic chemistry. These compounds are well-studied for their roles as chelating ligands in transition-metal-catalyzed reactions, coordination chemistry including materials science [109,110]. The challenge associated with the C-H functionalization of bidentate molecules is the finding strategy in the subduing the high activation barrier of rollover cyclometallation pathway. In this section we discuss the C(sp 2 )-H functionalization of the pyridine ring in bipyridine ring systems. In early 2009 Miura and co-workers [111] reported the rhodium-catalyzed regioselective reaction of aryl-Nheterocycles and aromatic imines with terminal silylacetylenes 209 to synthesize C-H-alkenylated products 210. The terminal silylacetylenes were employed as effective substrates for cata-lytic cross-dimerization reactions. The reaction was performed in the presence of [RhCl(cod)] 2 (3 mol %), taking PPh 3 or (4-ClC 3 H 4 ) 3 P as the ligand at 160 °C, for about 48 h (Scheme 39). This work provides an effective way for preparing C-H-alkenylated bipyridines 210.
In 2012, a hydroarylation of alkenes 211 and alkynes 212 with 2,2′-bipyridines 208 and 2,2′-biquinolines was reported by Chang and co-workers [112] in the presence of Rh(acac) 3 as catalyst, IMes·HCl (3 mol %) as ligand and t-BuONa (30 mol %) in toluene for 2 h (Scheme 40). The authors demonstrated theoretically and mechanistically the important role of the NHC ligand in the resultant catalyst Rh(NHC) for the hydroarylation of alkenes and alkynes with chelating 2,2-bipyridine and 2,2-biquinoline molecules. The experimental studies revealed that the trans-effect of the NHC ligand in the complex assisting in the reduced energy barrier of a rollover cyclometallation pathway and results in selective and efficient hydroarylation of the alkenes and alkynes. This was the first report for the role of a "rollover" cyclometallation pathway catalytically leading to double C-H bond functionalization of chelating mol- ecules under action of a Rh(NHC) system. Based on the computational studies and experimental data, the proposed mechanism (Scheme 40b) describes that the Rh(I) complex ligated to tert-butoxide and NHC (IMes·HCl) 215 is a catalytically active species. The Rh-hydride species 217 is formed after oxidative addition via C-H-bond cleavage followed by olefin insertion to form intermediate 218, which on subsequent reductive elimination results in the formation of monoalkylated bipyridine 219. This intermediate reenters into another cycle of hydroarylation by starting as bidentate complex 220 and finally furnishing the desired bishydroarylated product 213 (Scheme 40b).
Next, a protocol for the selective and catalytic C-H functionalization of N,N,N-tridentate chelating compounds using a rollover cyclometallation strategy was reported by the same group in 2016 [113]. The reaction involves the Rh-catalyzed alkylation of 2,2':6',2"-terpyridine 221 with 3,3-dimethyl-1-butene coupled in the presence of a catalytic amount of t-BuONa providing the mono-and dialkylated products in low combined yields. The alkylation of terpyridines with aliphatic olefins 222 afforded only anti-Markonikov linear products 223 (Scheme 41). The authors also expanded their study to tridentate heteroarenes. Delightfully, they observed the dialkylated Scheme 42: Pd-catalyzed rollover pathway in bipyridine-6-carboxamides C-H arylation.
products 223 in good yields. The plausible reaction mechanism (Scheme 41b) was explained by the formation of a cationic Rh-terpyridine complex 224 generated from terpyridine 221 and a Rh(NHC) species formed from the Rh(I) precursor and the NHC in the presence of an external base and successive decomplexation of 224 provides complex 225. The latter undergoes an initial key rollover cyclometallation followed by oxidative addition leading to the metal-hydride intermediate 226 which on olefin insertion and subsequent reductive elimination resulted in the monoalkylated rhoda complex 227. Complex 227 then undergoes recomplexation to form 228 and enters the subsequent catalytic cycle furnishing the bisalkylated product 223.
In 2018, Cheng and co-workers [114] reported a straight forward approach to 3'-aryl-2,2'-bipyridine-6-carboxamide derivatives 231 with exclusive selectivity starting from 2,2'bipyridine-6-carboxamides 229 under Pd catalysis (Scheme 42). The arylation reaction of N-butyl-2,2'-bipyridine-6-carboxamide with iodobenzene 230 in the presence of Pd(OAc) 2 as catalyst, Cs 2 CO 3 as a base in DMSO at 160 °C furnished the desired products 231 (Scheme 42). It was found that non-polar solvents resulted in good yields of the products 231. It is reported that 2,2'-bipyridine-6-carboxamides 229 can bind to the transition metal, such as Pd(II), to form stable N,N,N-chelates I (Scheme 42b). The amide moiety of the N,N,N-chelates I exerts a strong trans-effect which weakens the Pd(II)-pyridyl bond trans to the amide anion, thus, allowing the decomplexation to afford complex II which is key intermediate for furnishing the desired C-H functionalization product (Scheme 42b).
In 2019, Cheng and co-workers reported an approach for the C3-selective acylmethylation of [2,2"-bipyridine]-6-carboxamides 232 with sulfoxonium ylides 233 in the presence of a Rh(III) catalyst (Scheme 43) [115]. Sterically hindered amide directing groups were also well tolerated under the optimal conditions. A H/D exchange reaction exclusively at the C3-po- Recently, in 2020, Zhu and co-workers [116], developed a novel annulation reaction of bipyridine systems 211 with alkynes 239 via a Rh(III)-catalyzed dual C-H functionalization. The authors have initiated their studies with 6-bromo-2,2'bipyridine as their model substrate and with diphenylacetylene as coupling partner. The optimized conditions included [RhCp*Cl 2 ] 2 (5 mol %), AgOAc (2.5 equiv), NaOAc (5 equiv) in DCE, at 110 °C for 24 h to obtain the annulated product 240 (Scheme 44). The proposed mechanism (Scheme 44b) involves the formation of Rh(III) complex 241 by coordination of the bipyridine with rhodium and complex 241 via a rollover cyclometallation process gives the intermediate 242. It was suggested that the substitution at the 6 position of the bipyridine ring system facilitates the rollover cyclometallation process by weakening the Rh-N bond. Next, intermediate 242 coordinates with alkyne 239 to give the seven-membered rhodacycle 243. The excess Ag + help in the dissociation of the N-Rh bond in complex 243 and give the five-membered rhodacyclic intermediate 244 which again coordinates with the alkyne 239 furnishing another seven-membered rhodacyclic intermediate 245 or 246. Finally, reductive elimination delivers the desired product 240.
In the subsequent year, the same group reported a method for the rhodium-catalyzed acylmethylation of bipyridines [117]. The group has demonstrated a switchable reaction, wherein changing the additive can deliver the acylmethylated product 248 or the annulation product pyrido[2,3-a]indolizine 249 (Scheme 45). Under action of the Rh(III) catalyst, zinc acetate and PivOH as additives, the acylmethylation of bipyridines takes place at the C-2 position to furnish acylmethylated products 248 and the reaction was found suitable for various sub-strates. On the other hand, the usage of silver acetate as an additive provided the annulated (intramolecular cyclization of bipyridine) product 249.

Miscellaneous reactions C-H Borylation
Due to the broad utilities of arylboronic esters in organic synthesis, various protocols have been reported till date for their incorporation into an organic molecule. In 2017, Nakao and group reported a method for the iridium-catalyzed para-C-H borylation of pyridines using bis(pinacolato)diboron (250) for the synthesis of borylated pyridines 251, which are important intermediates for various derivatization reactions (Scheme 46) [118]. In common, site-selective borylations have been in less focus, due to the lack of suitable strategies, however, this group achieved the para-selective borylation of pyridines using a cooperative catalyst strategy. The authors used [Ir(cod)(OMe)] 2 as a metal catalyst, along with a sterically bulky Lewis acid such as methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) as a cooperative catalyst.
Later, in 2019, the same group reported a protocol for the selective C5(C3)-borylation of pyridines under iridium-Lewis acid bifunctional catalysis (Scheme 47) [119]. With the optimized conditions in hands, the authors screened for the substrate scope of substituted pyridines. Also, they employed the reported protocol for the late-stage functionalization of brompheniramine (252d), an antihistaminic drug.

C-H Silaboration
In 2011, a protocol for the synthesis of highly functionalized dihydropyridines via palladium-catalyzed silaboration providing silylated dihydropyridines 255 and 256 (Scheme 48) was developed by Suginome and co-workers [120]. This reaction involved a dearomatizing conversion of pyridines to dihydropyridines under mild conditions with the introduction of a silyl group on a carbon atom of pyridine ring. Various pyridines were subjected to this silaboration using the Pd/PCy 3 catalytic system providing the corresponding products in good yields. The proposed mechanism (Scheme 48b) involves the oxidative addition of silylboronic ester 254 to Pd(0) and coordination of pyridine 1 providing the intermediate 257 which on further regioselective insertion of pyridine into the Pd-B bond resulted in the π-allyl palladium complex 258. Subsequent reductive elimination furnishes the silaboration products 255 and 256 with the regeneration of Pd(0).

Conclusion
Significant progress has been made in the area of ortho-and distal C-H-functionalization of pyridines, as evidenced by the reactions outlined in this review. The previous research and their mechanistic insight provided us with more information to approach the new avenue of catalytic C−H functionalization of the pyridine nucleus. The challenges still remain for the distal C-H functionalization, particularly at the C4 position. Even the directing group on pyridine ring system has been less explored for ortho-or distal C-H functionalization. Although the C-H functionalization with transition-metal catalysis and rare earth metal catalysis has advanced, the functionalization of the pyridine ring system can further be explored by employing new catalytic systems and merging of different strategies. Taking this into account, we hope that the efforts for the development of novel protocols for the preparation and incorporation of functionalized pyridine scaffolds will continue and could be applicable for applications in industry.